University of Groningen PET Imaging of Beta-Adrenoceptors in Human
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University of Groningen PET imaging of beta-adrenoceptors in human brain: A realistic goal or a mirage? van Waarde, Aaren; Vaalburg, W.; Doze, Petra; Bosker, Fokko; Elsinga, P.H Published in: Current Pharmaceutical Design IMPORTANT NOTE: You are advised to consult the publisher's version (publisher's PDF) if you wish to cite from it. Please check the document version below. Document Version Final author's version (accepted by publisher, after peer review) Publication date: 2004 Link to publication in University of Groningen/UMCG research database Citation for published version (APA): van Waarde, A., Vaalburg, W., Doze, P., Bosker, F., & Elsinga, P. H. (2004). PET imaging of beta- adrenoceptors in human brain: A realistic goal or a mirage? Current Pharmaceutical Design, 10(13), 1519 - 1536. 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Download date: 03-10-2021 Current Pharmaceutical Design, 2004, 10, 1519-1536 1519 PET Imaging of Beta-Adrenoceptors in Human Brain: A Realistic Goal or a Mirage? Aren van Waarde*, Willem Vaalburg, Petra Doze, Fokko J.Bosker1 and Philip H. Elsinga PET Center and 1Dept. Biological Psychiatry, Groningen University Hospital P.O.Box 30001, Hanzeplein 1 9700 RB Groningen The Netherlands Abstract: Beta-adrenoceptors are predominantly located in the cerebral cortex, nucleus accumbens and striatum. At lower densities, they are also present in amygdala, hippocampus and cerebellum. Beta-2 sites regulate glial proliferation during ontogenic development, after trauma and in neurodegenerative diseases. The densities of beta-1 adrenoceptors are changed by stress, in several mood disorders (depression, excessive hostility, schizophrenia) and during treatment of patients with antidepressants. A technique for beta-adrenoceptor imaging in the human brain is not yet available. Although 24 (ant)agonists have been labeled with either 11C or 18F and some of these are successful myocardial imaging agents, only two (S-1’-18F- fluorocarazolol and S-1’-18F-fluoroethylcarazolol) could actually visualize ß-adrenoceptors within the central nervous system. Unfortunately, these radiopharmaceuticals showed a positive Ames test. They may be mutagenic and cannot be employed for human studies. Screening of more than 150 beta-blockers described in the literature yields only two compounds (exaprolol and L643,717) which can still be radiolabeled and evaluated for ß-adenoceptor imaging. However, other imaging techniques could be examined. Cerebral ß-adrenoceptors might be labeled after temporary opening of the blood-brain barrier (BBB) and simultaneous administration of a hydrophilic ligand such as S-11C-CGP12388. Another approach to target ß-adrenoceptor ligands to the CNS is esterification of a myocardial imaging agent (such as 11C-CGP12177), resulting in a lipophilic prodrug which can cross the BBB and is split by tissue esterases. BBB opening is not feasible in healthy subjects, but the prodrug approach may be successful and deserves to be explored. Key Words: Beta-adrenoceptors, positron emission tomography, human, brain, depression, multiple sclerosis, radiopharma- ceuticals, imaging. INTRODUCTION in the first decade of the twentieth century [51]. Later, it was In the autonomic nervous system, two networks can be shown that the adrenoceptor family could be divided in two distinguished which regulate the internal environment to populations, called a - and b-adrenoceptors [8]. The former maintain a steady-state (homeostasis): the sympathetic and induce activation of the uterus and vasoconstriction, the latter inhibition of the uterus and vasodilation. Later still, ß- the parasympathetic system. The latter network maintains basal functions (heart rate, respiration, etc.) under normal adrenoceptors were classified in two different subtypes: ß1 conditions, whereas the former responds to threatening situa- and ß2 [136]. Beta-1 agonists stimulate cardiac contractility and lipolysis, whereas beta-2 agonists cause bronchodilation tions (hypoglycemia, hypoxia, sudden changes in the environ- ment). Sympathetic activation results e.g. in increased and vasodepression. Since then, ß1-adrenoceptors involved in cardiac output, body temperature and blood glucose in order lipolysis have been reclassified as ‘atypical’ or ß3-adreno- to respond adequately in case of an emergency. ceptors [14]. A fourth subtype, the putative ß4-adrenoceptor, has been suggested to exist in myocardial and adipose tissue The physiological responses resulting from activation of [84, 127]. Blocking this subtype requires much higher the sympathetic nervous system are mediated by the neuro- concentrations of ß-adrenoceptor antagonists than those transmitter noradrenalin and the hormone adrenalin. These required to block ß1- or ß2-adrenoceptors. catecholamines originate from the amino acid tyrosine. Since responses to stressful situations occur all over the Noradrenalin is synthesized in nerve endings, while adrena- body, ß-adrenoceptors are present in many different organs. lin is produced mainly in the chromaffin cells of the adrenal Stimulation of myocardial receptors increases heart rate and medulla. Both compounds activate specific membrane recep- contractile force, resulting in enhanced cardiac output [32]. tors called adrenoceptors. The interaction of noradrenalin Stimulation of pulmonary ß-adrenoceptors causes bronchodi- with these receptors was discovered by Sir Henry Dale lation and increased blood flow, resulting in enhanced oxygen uptake [16]. Beta-adrenoceptors in the pancreas regulate the secretion of glucagon [135], while those in the *Address correspondence to this author at the PET Center, Groningen University Hospital, P.O. Box 30001, Hanzeplein 1, 9700 RB Groningen, liver and kidney control glycogenolysis and glucose release The Netherlands; Tel: +31-50-3613215; Fax: +31-50-3611687; [125, 91]. The overall effect of stimulation of these receptors E-mail: [email protected] is an increased availability of glucose and an increased 1381-6128/04 $45.00+.00 © 2004 Bentham Science Publishers Ltd. 1520 Current Pharmaceutical Design, 2004, Vol. 10, No. 13 Waarde et al. capacity of tissues to use glucose as a fuel. Beta-adreno- interpret because of the heterogeneity of the patient groups ceptors in the spleen are involved in the stress-induced (e.g., large differences in medication) and the fact that many augmentation of circulatory blood volume and lymphoid cell different radioligands were used in the receptor assays. Later mobilization [232, 196]. The secretion of many glands, studies employing more stringent inclusion criteria demons- including the lacrimal [1], salivary [188], thyroid [9] and trated ß-adrenoceptor decreases in several cortical areas, not pituitary [210] glands, is also under ß-adrenergic control. only in antidepressant-treated but also in drug-free depressed Physiological and behavioral responses to noradrenalin in patients [55, 149, 202]. After long-term treatment with the central nervous system are regulated predominantly by antidepressants, cerebral ß-adrenoceptors are downregulated two different nuclei in the brain stem: the locus coeruleus in human brain [56, 11]. and the lateral tegmental neurons. The former has very broad Several other disorders of mood and behavior, such as projections throughout the brain. Much less noradrenergic schizophrenia [130, 121], excessive hostility [256, 222], neurons project from the lateral tegmental neurons to the premenstrual dysphoria [95] and chronic alcohol abuse [94] brain stem, spinal cord and thalamus. While the lateral have been reported to be accompanied by abnormal ß- tegmental neurons contribute to the integration of autonomic adrenoceptor densities and/or coupling of ß-adrenoceptors to functions (blood pressure and heart rate), the projections of the Gs protein. Low doses of lipophilic ß-blockers proved the locus coeruleus play an important role in behavioral often effective in the suppression of psychosis or anxiety and responses such as orientation, and reactions to sudden the reduction of aggressive behavior in chronic psychiatric contrasting or aversive sensori stimuli [167]. patients [96, 15, 75]. Cerebral ß-adrenoceptors are involved in several physio- Neurodegenerative diseases may also be associated with logical functions, such as respiratory [12, 81], cardiovascular abnormal ß-adrenoceptor function. In some patients with [231] and renal [132] sympathetic nervous control. Further- Parkinson’s disease, an increased number of ß1 adrenocep- more, ß-adrenoceptors located on glial cells regulate (injury- tors was found in the pre-frontal cortex [38]. Alzheimer’s induced) astrogliosis and microglial